Characterizing novel metabolic pathways of melatonin receptor agonist agomelatine using metabolomic approaches

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• 作者：Xing Liu^a ; ¹ ; Yuan-Fu Lu^b ; ¹ ; Xinfu Guan^c ; Mingkun Zhao^d ; ^e ; Jin Wang^d ; Feng Li^a ; ^{fl3@bcm.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：CYP450 ; cytochrome P450 ; HLM ; human liver microsomes ; AGM ; agomelatine ; KCZ ; ketoconazole ; NF ; α-naphthoflavone ; GSH ; reduced glutathione ; NAc ; N-acetyl cysteine ; OPLS-DA ; orthogonal projection to latent structures-discriminant analysis ; UHPLC ; ultra-high-performance liquid chromatography ; QTOFMS ; quadrupole time-of-flight mass spectrometry
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：1 June 2016
• 年：2016
• 卷：109
• 期：Complete
• 页码：70-82
• 全文大小：4155 K

文摘

Agomelatine (AGM), an analog of melatonin, is a potential agonist at melatonin receptors 1/2 and a selective antagonist at 5-hydroxytryptamine 2C receptors. AGM is widely used for the treatment of major depressive episodes in adults. However, multiple adverse effects associated with AGM have been reported in clinical practice. It is little known about AGM metabolism in vitro and in vivo, although metabolism plays a pivotal role in its efficacy and safety. To elucidate metabolic pathways of AGM, we systemically investigated AGM metabolism and its bioactivation in human liver microsomes (HLM) and mice using metabolomic approaches. We identified thirty-eight AGM metabolites and adducts, among which thirty-two are novel. In HLM, we uncovered five GSH-trapped adducts and two semicarbazide-trapped aldehydes. Moreover, we characterized three N-acetyl cysteine conjugated-AGM adducts in mouse urine and feces, which were formed from the degradation of AGM_GSH adducts. Using recombinant CYP450 isoenzymes and chemical inhibitors, we demonstrated that CYP1A2 and CYP3A4 are primary enzymes contributing to the formation of AGM_GSH adducts and AGM_hydrazones. This study provided a global view of AGM metabolism and identified the novel pathways of AGM bioactivation, which could be utilized for further understanding the mechanism of adverse effects related to AGM and possible drug–drug interactions.